Mast cells express c-kit and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of the c-kit receptor to initiate the signal transduction events that result in cell proliferation. We thus screened the peripheral blood mononuclear cells of patients with indolent mastocytosis (IM), mastocytosis with an associated hematologic disorder (MAHD), aggressive mastocytosis (AM), solitary mastocytoma, and CMML unassociated with mastocytosis for a mutation in the c-kit receptor using single strand conformational polymorphism (SSCP) analysis. In our initial analysis (Nagata et. al, PNAS, USA 1995, 92:10560-10564) 4 out of 4 patients with MAHD with predominantly myelodysplastic features had an A~T substitution at nucleotide 2468 of c-kit mRNA that causes an Asp-816~Val substitution in the catalytic domain of the c-kit receptor. This mutation was not identified in other categories of mastocytosis or in 67 of 67 controls. These findings were confirmed in the genomic DNA of a patient with MAHD. Pedigree analysis of 2 families suggests that the mutation is somatic. Screening of additional mastocytosis patients (46 total) has resulted in the following findings: 100% of patients with MAHD have the Asp(816)Val mutation in the c-kit receptor (n=8), 0% of patients with urticaria pigmentosa alone have this mutation (n=6), and 20% of patients with IM (6/30) have the Asp(816)Val mutation. Of this latter group of IM patients, disease was characterized by more severe manifestations and clinical features suggestive of early myelodysplastic or myeloproliferative syndromes. These patients more commonly had osteosclerotic bone involvement, a clinical feature primarily seen in the patients with MAHD, along with immunoglobulinopathies and peripheral blood abnormalities.